Isosorbide mononitrate 40mg Tablets

1. Name Of The Medicinal Product

Isosorbide mononitrate 40mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 40 mg of isosorbide mononitrate.

Excipient: 10 mg of lactose monohydrate/tablet

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet

Isosorbide mononitrate 40mg tablets:

White to off white, round, flat, bevelled edge uncoated tablets, debossed with 'AT' on one side and break line on the other side. The tablets can be divided in to equal halves.

4. Clinical Particulars

4.1 Therapeutic Indications

Prophylactic treatment of angina pectoris.

4.2 Posology And Method Of Administration

For oral administration.

Adults

The usual dose of Isosorbide mononitrate is 1 tablet of Isosorbide mononitrate 20 mg, 2 to 3 times daily. If result is not adequate, the dose may be increased to 1 tablet of Isosorbide mononitrate 40 mg, 2 to 3 times daily.

The maximum dose is 3 tablets isosorbide mononitrate 40 mg per day.

In order to prevent possible initial undesirable effect, it may be adequate to initiate treatment with possible lowest dose and slowly increase to the required dose.

To prevent tolerance, it is recommended that the dosage be kept as low as possible and that a sufficiently long nitrate-free interval is ensured to restore sensitivity (first dose in the morning and last dose late in the afternoon, e.g. at 8 am and 15 pm).

The tablet should be swallowed whole with sufficient liquid to take. (e.g. 1 glass of water)

The duration of application is decided by the treating physician.

As with other nitrates, treatment with isosorbide mononitrate must not be stopped suddenly. Both the dosage and frequency of intake should be tapered off slowly (see section 4.4).

Elderly

There are no indications that adjustment is necessary.

Children

There are as yet no data on the safety and efficacy of isosorbide mononitrate in children

4.3 Contraindications

Hypersensitivity to nitrates or to any of the excipients.

Isosorbide mononitrate should not be used in cases of acute myocardial infarction with low filling pressure, acute circulatory failure (shock, vascular collapse), or hypertrophic obstructive cardiomyopathy (HOCM), low cardiac filling pressures, aortic/mitral valve stenosis and diseases associated with a raised intra-cranial pressure e.g following a head trauma and including cerebral haemorrhage.

Isosorbide mononitrate should not be used in patients with marked anaemia, severe hypotension, closed angle glaucoma or hypovolaemia.

Phosphodiesterase type-5 inhibitors (eg sildenafil, tadalafil and vardenafil) have been shown to potentiate the hypotensive effects of nitrates, and their co-administration with nitrates or nitric oxide donors is therefore contraindicated (see section 4.5)

4.4 Special Warnings And Precautions For Use

In the event of an acute angina attack, a sublingual treatment such as a GTN spray or tablet should be used instead of Isosorbide mononitrate.

Vascular dilatation can precipitate venous pooling with decreased return to the heart, hypotension and reflex tachycardia. Therefore, oral nitrates should not be used by patients who are sensitive to the effects of hypotension, such as those with pre-existing hypotension, shock, vascular collapse or significant cerebrovascular disease, significant anaemia or hypothyroidism. Isosorbide mononitrate should be used with caution in patients who have a recent history of myocardial infarction, or who are suffering from hypothermia, malnutrition and severe liver or renal disease. For the same reason, oral nitrates should also be used with caution in patients with angina due to other causes angina or with pre-existing hyperdynamic conditions.

Since oral nitrates cause venous dilatation they should not be used in patients with increased intracranial pressure. (With high dose i.v. administration of Glyceroltrinitrate a further increase in pressure was observed)

Development of tolerance and cross tolerance to other nitrates was described. A continuous administration of high doses should be avoided. The lowest effective dose should be used.

Symptoms of circulatory collapse may arise after first dose, particularly in patients with labile circulation.

Isosorbide mononitrate may give rise to postural hypotension and syncope in some patients. Severe postural hypotension with is frequently observed with concomitant consumption of alcohol.

Hypotension induced by nitrates may be accompanied by paradoxical bradycardia and increased angina.

Treatment with Isosorbide mononitrate, as with any other nitrate, should not be stopped suddenly. Both the dosage and frequency should be tapered gradually

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The antihypertensive effect of Isososrbide mononitrate will increase when it is used concomitantly with phosphodiesterase type 5 inhibitors, which are used in erectile dysfunction. This can lead to life-threatening vascular complications. Patients treated with isosorbide mononitrate must not use phosphodiesterase type 5 inhibitors (see 4.3).

Concomitant use of drugs with an antihypertensive action, e.g. beta blockers, calcium antagonists, vasodilators (including neuroleptics and tricyclic antidepressants), alprostadil, aldesleukin, antihypertensives, diuretics, angiotensin II receptor antagonists etc. and / or alcohol can potentiate the hypotensive effect of Isosorbide mononitrate. This can also occure with buse of neuroleptics and tricyclic antidepressant.

Reports suggest that concomitant use of Isosorbide mononitrate increases the blood levels of dihydroergotamine and that the hypertensive effect is potentiated.

There are no data available on the interaction with food.

4.6 Pregnancy And Lactation

Pregnancy

Data on the use of isosorbide mononitrate during pregnancy are insufficient to be able to assess the possible harmful effect. Limited data from animal studies indicate no adverse effects on the pregnancy or the unborn child. As precautionary measure, it is preferable to avoid the use of isosorbide mononitrate during pregnancy.

Breastfeeding

There are no data on passage of isosorbide mononitrate in human milk, but some excretion seems likely. The effects of this exposure on a nursing infant are unknown. As precautionary measure, breast-feeding should be discontinued during treatment with isosorbide mononitrate.

Fertility

Animal data do not suggest an effect of the treatment of isosorbide mononitrate on male and female fertility. Human data are lacking.

4.7 Effects On Ability To Drive And Use Machines

Isosorbide mononitrate may occasionally trigger a drop in blood pressure, which can cause dizziness. This is particularly true at the start of treatment or increasing doses.

4.8 Undesirable Effects

Most undesirable effects are pharmacologically mediated and are dose dependent. Headache occurs in approximately 25% of patients at the start of treatment and can be attributed to the vasodilatory effect of the preparation; the headache usually disappears within about one week. Hypotension (with dizziness and nausea) has been reported, but this disappears with continued treatment

The frequencies of adverse events are ranked according to the following: Very common ( Common ( Uncommon ( Rare ( Very rare (<1/10,000), Not known (cannot be estimated from the available data)
System Organ Class	Frequency	Adverse event
Nervous System Disorders	Very common	Headache
Common	Dizziness, Somnolence
Rare	Syncope
General disorders and administration site conditions	Common	Asthenia
Vascular Disorders	Common	Hypotension
Uncommon	Collapse with worsening of symptoms of angina pectoris (sometimes accompanied by bradyarrhythmia and syncope); Transient hypoxemia with myocardial hypoxia in patients with coronary artery disease.
Cardiac disorders:	Common	Tachycardia
Not known	Paroxysmal bradycardia
Gastrointestinal disorders	Common	Nausea
Uncommon	Vomiting, diarrhoea
	Very rare	Dyspepsia*
Skin and subcutaneous tissue disorders	Rare	Rash, pruritus
Not known	Exfoliative dermatitis, flushing, allergic skin reactions**

* Most likely due to a nitrate induced sphincter relaxation

** Sometimes severe

The frequency of headache can be reduced by starting treatment with 30 mg during the first 2-4 days and gradually titrating the dose upwards as necessary. A drop in blood pressure can lead to reflex tachycardia, dizziness and fainting.

4.9 Overdose

Signs and symptoms:

Headache, hypotension, nausea, vomiting, sweating, tachycardia, dizziness, anxiety, hot and red skin, blurred vision and syncope. An increase in intracranial pressure with confusion and neurological deficit occurs uncommonly. Methaemoglobinaemia (cyanosis, hypoxaemia, agitation, respiratory depression, convulsions, cardiac arrhythmias, circulatory insufficiency, increased intracranial pressure) occurs rarely.

Treatment

The following treatments are intended only as guidelines and are at the discretion of the treating physician.

General procedure:

• Stop using isosorbide mononitrate.

• Consider absorption-reducing therapy (administration of activated charcoal) and in case of suspected severe intoxication consider flushing of the stomach (where practicable within one hour after ingestion).

• General procedure in case of incident of nitrate-related low blood pressure:

- Put the patient in horizontal position with the legs up and lower the head.

- Give oxygen.

- Maintain plasma volume.

In case of persistent hypotension

• Administration of norepinephrine HCl or dopamine.

Treatment for methemoglobinemia

• Administration of antidote:

- methylene blue: up to 50 ml of a 1% solution i.v.;

- vitamin C: 1 g p.o. or as sodium salt i.v;

- toluidine blue: initially 2 - 4 mg/kg body weight strictly i.v.; if necessary repeated several times with a time lag of one hour with 2 mg/kg body weight.

• If necessary, apply artificial respiration.

• In severe refractory methemoglobinemia (metHEB> 70%) consider hemodialysis, exchange transfusion.

In case of signals of a respiratory and circulatory arrest, start reanimation immediately.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: VASODILATORS USED IN CARDIAC DISEASES; Organic nitrates

ATC code: C01DA14

This preparation is a prolonged release form of Isosorbide mononitrate, an active metabolite of isosorbide dinitrate. Nitro-compounds cause a dose-dependent relaxation of smooth muscle. The therapeutic effect is dependent on dose and individual sensitivity.

Low doses cause dilatation of the veins and a decreased venous return to the heart (reduced preload). High doses also cause arterial dilatation and decreased vascular resistance (reduced afterload). Isosorbide mononitrate reduces the load on the heart by venous and arterial dilatation and can have a direct vasodilatory effect on the coronary arteries. By reducing end-diastolic pressure and volume, it lowers the pressure inside the ventricle and thus improves the subendocardial blood flow. The net effect of isosorbide mononitrate is a reduced load on the heart and better oxygen supply to the myocardium.

Isosorbide mononitrate is intended for use in the prophylactic treatment of angina pectoris.

Continuous treatment with nitro-preparations is associated with the development of tolerance. For this reason, the tablets should be taken once a day in order to obtain an interval with low nitrate concentration.

5.2 Pharmacokinetic Properties

Isosorbide mononitrate is rapidly absorbed and peak plasma levels are reached approximately 1 hour after oral dosing.

Following oral administration, bioavailability of Isosorbide mononitrate is 100%. It does not undergo a first-pass effect.

Isosorbide mononitrate is eliminated from plasma with a half-life of approximately 5.1 hours. It is metabolised to isosorbide-5-MN-glucuronide, which has a half-life of approximately 2.5 hours. It is also excreted unchanged in the urine.

After multiple oral doses, plasma levels are consistent with predictions based on the kinetic parameters of a single dose.

5.3 Preclinical Safety Data

Non clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose monohydrate

Microcrystalline cellulose (PH 102) (E460)

Sodium starch glycolate (type-A)

Colloidal anhydrous silica (E551)

Magnesium stearate (E470b)

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Store below 30°C.

Store in original container

6.5 Nature And Contents Of Container

Al/PVC and Al/PVC-PVDC blister with 20, 30, 40, 50, 80, 90, 100 or 500 Tablets in a carton.

Pack sizes: 20, 30, 40, 50, 80, 90, 100 or 500 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Accord Healthcare Limited,

Sage House, 319, Pinner Road,

North Harrow, Middlesex,

HA1 4HF,

United Kingdom

8. Marketing Authorisation Number(S)

PL 20075/0313

9. Date Of First Authorisation/Renewal Of The Authorisation

16/03/2011

10. Date Of Revision Of The Text

16/03/2011

11 DOSIMETRY

IF APPLICABLE

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

IF APPLICABLE

Makena

hydroxyprogesterone caproate

Dosage Form: injection
FULL PRESCRIBING INFORMATION

Indications and Usage for Makena

Makena is a progestin indicated to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. The effectiveness of Makena is based on improvement in the proportion of women who delivered <37 weeks of gestation. There are no controlled trials demonstrating a direct clinical benefit, such as improvement in neonatal mortality and morbidity.

Limitation of use: While there are many risk factors for preterm birth, safety and efficacy of Makena has been demonstrated only in women with a prior spontaneous singleton preterm birth. It is not intended for use in women with multiple gestations or other risk factors for preterm birth.

Makena Dosage and Administration

Dosing

• Administer intramuscularly at a dose of 250 mg (1 mL) once weekly (every 7 days) by a healthcare provider


• Begin treatment between 16 weeks, 0 days and 20 weeks, 6 days of gestation


• Continue administration once weekly until week 37 (through 36 weeks, 6 days) of gestation or delivery, whichever occurs first

Preparation and Administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Makena is a clear, yellow solution. Do not use if solid particles appear or if the solution is cloudy.

Instructions for administration:

1. Clean the vial top with an alcohol swab before use.


2. Draw up 1 mL of drug into a 3 mL syringe with an 18 gauge needle.


3. Change the needle to a 21 gauge 1 1/2 inch needle.


4. After preparing the skin, inject in the upper outer quadrant of the gluteus maximus. The solution is viscous and oily. Slow injection (over one minute or longer) is recommended.


5. Applying pressure to the injection site may minimize bruising and swelling.

Discard any unused product 5 weeks after first use.

Dosage Forms and Strengths

Makena (250 mg/mL) is a sterile solution of hydroxyprogesterone caproate in castor oil for injection. Each 5 mL multidose vial contains 1250 mg hydroxyprogesterone caproate.

Contraindications

Do not use Makena in women with any of the following conditions:

• Current or history of thrombosis or thromboembolic disorders


• Known or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions


• Undiagnosed abnormal vaginal bleeding unrelated to pregnancy


• Cholestatic jaundice of pregnancy


• Liver tumors, benign or malignant, or active liver disease


• Uncontrolled hypertension

Warnings and Precautions

Thromboembolic Disorders

Discontinue Makena if an arterial or deep venous thrombotic or thromboembolic event occurs.

Allergic Reactions

Allergic reactions, including urticaria, pruritus and angioedema, have been reported with use of Makena or with other products containing castor oil. Consider discontinuing the drug if such reactions occur.

Decrease in Glucose Tolerance

A decrease in glucose tolerance has been observed in some patients on progestin treatment. The mechanism of this decrease is not known. Carefully monitor prediabetic and diabetic women while they are receiving Makena.

Fluid Retention

Because progestational drugs may cause some degree of fluid retention, carefully monitor women with conditions that might be influenced by this effect (e.g., preeclampsia, epilepsy, migraine, asthma, cardiac or renal dysfunction).

Depression

Monitor women who have a history of clinical depression and discontinue Makena if clinical depression recurs.

Jaundice

Carefully monitor women who develop jaundice while receiving Makena and consider whether the benefit of use warrants continuation.

Hypertension

Carefully monitor women who develop hypertension while receiving Makena and consider whether the benefit of use warrants continuation.

Adverse Reactions

For the most serious adverse reactions to the use of progestins, see Warnings and Precautions (5).

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In a vehicle (placebo)-controlled clinical trial of 463 pregnant women at risk for spontaneous preterm delivery based on obstetrical history, 310 received 250 mg of Makena and 153 received a vehicle formulation containing no drug by a weekly intramuscular injection beginning at 16 to 20 weeks of gestation and continuing until 37 weeks of gestation or delivery, whichever occurred first.1 [See Clinical Studies (14.1).]

Certain pregnancy-related fetal and maternal complications or events were numerically increased in the Makena-treated subjects as compared to control subjects, including miscarriage and stillbirth, admission for preterm labor, preeclampsia or gestational hypertension, gestational diabetes, and oligohydramnios (Tables 1 and 2).

Table 1 Selected Fetal Complications
1 N = Total number of subjects enrolled prior to 20 weeks 0 days. 2 N = Total number of subjects at risk ≥20 weeks.
Pregnancy Complication	Makena	Control
	n/N	n/N
Miscarriage (<20 weeks)1	5/209	0/107
Stillbirth (≥20 weeks)2	6/305	2/153

Table 2 Selected Maternal Complications
1 Other than delivery admission.
Pregnancy Complication	Makena N=310 %	Control N=153 %
Admission for preterm labor1	16.0	13.8
Preeclampsia or gestational hypertension	8.8	4.6
Gestational diabetes	5.6	4.6
Oligohydramnios	3.6	1.3

Common Adverse Reactions:

The most common adverse reaction was injection site pain, which was reported after at least one injection by 34.8% of the Makena group and 32.7% of the control group. Table 3 lists adverse reactions that occurred in ≥2% of subjects and at a higher rate in the Makena group than in the control group.

Table 3 Adverse Reactions Occurring in ≥2% of Makena-Treated Subjects and at a Higher Rate than Control Subjects
Preferred Term	Makena N=310 %	Control N=153 %
Injection site pain	34.8	32.7
Injection site swelling	17.1	7.8
Urticaria	12.3	11.1
Pruritus	7.7	5.9
Injection site pruritus	5.8	3.3
Nausea	5.8	4.6
Injection site nodule	4.5	2.0
Diarrhea	2.3	0.7

In the clinical trial, 2.2% of subjects receiving Makena were reported as discontinuing therapy due to adverse reactions compared to 2.6% of control subjects. The most common adverse reactions that led to discontinuation in both groups were urticaria and injection site pain/swelling (1% each).

Pulmonary embolus in one subject and injection site cellulitis in another subject were reported as serious adverse reactions in Makena-treated subjects.

Drug Interactions

No drug-drug interaction studies were conducted with Makena.

Drugs Metabolized by CYP1A2, CYP2A6 and CYP2B6

The metabolism of drugs metabolized by CYP1A2 (such as theophylline, tizadine, clozapine), CYP2A6 (such as acetaminophen, halothane, nicotine) and CYP2B6 (such as efavirenz, bupropion, methadone) may be increased during treatment with Makena [See Clinical Pharmacology (12.3)] .

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B: There are no adequate and well-controlled studies of Makena use in women during the first trimester of pregnancy. Data from a vehicle (placebo)-controlled clinical trial of 310 pregnant women who received Makena at weekly doses of 250 mg by intramuscular injection in their second and third trimesters1, as well as long-term (2-5 years) follow-up safety data on 194 of their infants 2, did not demonstrate any teratogenic risks to infants from in utero exposure to Makena.

Reproduction studies have been performed in mice and rats at doses up to 95 and 5, respectively, times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Makena.

Makena administration produced embryolethality in rhesus monkeys but not in cynomolgus monkeys exposed to 1 and 10 times the human dose equivalent every 7 days between days 20 and 146 of gestation. There were no teratogenic effects in either species.

Labor and Delivery

Makena is not intended for use to stop active preterm labor. The effect of Makena in active labor is unknown.

Nursing Mothers

Discontinue Makena at 37 weeks of gestation or upon delivery. Detectable amounts of progestins have been identified in the milk of mothers receiving progestin treatment. Many studies have found no adverse effects of progestins on breastfeeding performance, or on the health, growth, or development of the infant.

Pediatric Use

Makena is not indicated for use in children. Safety and effectiveness in pediatric patients less than 16 years of age have not been established. A small number of women under age 18 years were studied; safety and efficacy are expected to be the same in women aged 16 years and above as for users 18 years and older. [See Clinical Studies (14).]

Geriatric Use

Makena is not intended for use in postmenopausal women. Safety and effectiveness in postmenopausal women have not been established.

Renal Impairment

No studies have been conducted to examine the pharmacokinetics of Makena in patients with renal impairment.

Hepatic Impairment

No studies have been conducted to examine the pharmacokinetics of Makena in patients with hepatic impairment. Makena is extensively metabolized and hepatic impairment may reduce the elimination of Makena.

Overdosage

There have been no reports of adverse events associated with overdosage of Makena in clinical trials. In the case of overdosage, the patient should be treated symptomatically.

Makena Description

The active pharmaceutical ingredient in Makena is hydroxyprogesterone caproate.

The chemical name for hydroxyprogesterone caproate is pregn-4-ene-3,20-dione, 17[(1-oxohexyl)oxy]. It has an empirical formula of C27H40O4 and a molecular weight of 428.60. Hydroxyprogesterone caproate exists as white to practically white crystals or powder with a melting point of 120°-124°C.

The structural formula is:

Makena is a clear, yellow, sterile, non-pyrogenic solution for intramuscular injection. Each 5 mL multidose vial contains hydroxyprogesterone caproate USP, 250 mg/mL (25% w/v), in castor oil USP (28.6% v/v) and benzyl benzoate USP (46% v/v) with the preservative benzyl alcohol NF (2% v/v).

Makena - Clinical Pharmacology

Mechanism of Action

Hydroxyprogesterone caproate is a synthetic progestin. The mechanism by which hydroxyprogesterone caproate reduces the risk recurrent preterm birth is not known.

Pharmacodynamics

No specific pharmacodynamic studies were conducted with Makena.

Pharmacokinetics

Absorption: Peak serum levels of hydroxyprogesterone caproate appeared after 3-7 days in non-pregnant female subjects following a single intramuscular injection of 1000 mg hydroxyprogesterone caproate. Based on pharmacokinetic analysis of five non-pregnant female subjects who received a single intramuscular administration of 1000 mg hydroxyprogesterone caproate, the mean (±SD) Cmax is estimated to be 27.8 (±5.3) ng/mL, and the Tmax is estimated to be 4.6 (±1.7) days. The elimination half-life of hydroxyprogesterone caproate was 7.8 (±3.0) days. Once-weekly intramuscular administration of 1000 mg hydroxyprogesterone caproate to non-pregnant women resulted in trough concentration of 60.0 (±14) ng/mL after 13 weeks. The pharmacokinetics of the 250 mg dose of hydroxyprogesterone caproate has not been evaluated.

Distribution: Hydroxyprogesterone caproate binds extensively to plasma proteins including albumin and corticosteroid binding globulins.

Metabolism: In vitro studies have shown that hydroxyprogesterone caproate can be metabolized by human hepatocytes, both by phase I and phase II reactions. Hydroxyprogesterone caproate undergoes extensive reduction, hydroxylation and conjugation. The conjugated metabolites include sulfated, glucuronidated and acetylated products. In vitro data indicate that the metabolism of hydroxyprogesterone caproate is predominantly mediated by CYP3A4 and CYP3A5. The in vitro data indicate that the caproate group is retained during metabolism of hydroxyprogesterone caproate.

Excretion: Both conjugated metabolites and free steroids are excreted in the urine and feces, with the conjugated metabolites being prominent. Following intramuscular administration to pregnant women at 10-12 weeks gestation, approximately 50% of a dose was recovered in the feces and approximately 30% recovered in the urine.

Specific Populations

Renal Impairment: The effect of renal impairment on the pharmacokinetics of Makena has not been evaluated.

Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of Makena has not been evaluated.

Drug Interactions

Cytochrome P450 (CYP) enzymes: An in vitro study using human liver microsomes and CYP isoform-selective substrates indicated that hydroxyprogesterone caproate increased the metabolic rate of CYP1A2, CYP2A6, and CYP2B6 by approximately 80%, 150%, and 80%, respectively. The clinical implication of this in vitro metabolic acceleration is not well understood.

In vitro data indicated that therapeutic concentration of hydroxyprogesterone caproate is not likely to inhibit the activity of CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.

The metabolic induction potential of hydroxyprogesterone caproate has not been evaluated.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Hydroxyprogesterone caproate has not been adequately evaluated for carcinogenicity.

No reproductive or developmental toxicity or impaired fertility was observed in a multigenerational study in rats. Makena administered intramuscularly, at gestational exposures up to 5 times the recommended human dose, had no adverse effects on the parental (F0) dams, their developing offspring (F1), or the latter offspring's ability to produce a viable, normal second (F2) generation.

Clinical Studies

Clinical Trial to Evaluate Reduction of Risk of Preterm Birth

In a multicenter, randomized, double-blind, vehicle (placebo)-controlled clinical trial, the safety and effectiveness of Makena for the reduction of the risk of spontaneous preterm birth was studied in women with a singleton pregnancy (age 16 to 43 years) who had a documented history of singleton spontaneous preterm birth (defined as delivery at less than 37 weeks of gestation following spontaneous preterm labor or premature rupture of membranes).1 At the time of randomization (between 16 weeks, 0 days and 20 weeks, 6 days of gestation), an ultrasound examination had confirmed gestational age and no known fetal anomaly. Women were excluded for prior progesterone treatment or heparin therapy during the current pregnancy, a history of thromboembolic disease, or maternal/obstetrical complications (such as current or planned cerclage, hypertension requiring medication, or a seizure disorder).

A total of 463 pregnant women were randomized to receive either Makena (N=310) or vehicle (N=153) at a dose of 250 mg administered weekly by intramuscular injection starting between 16 weeks, 0 days and 20 weeks, 6 days of gestation, and continuing until 37 weeks of gestation or delivery. Demographics of the Makena-treated women were similar to those in the control group, and included: 59.0% Black, 25.5% Caucasian, 13.9% Hispanic and 0.6% Asian. The mean body mass index was 26.9 kg/m2.

The proportions of women in each treatment arm who delivered at <37 (the primary study endpoint), <35, and <32 weeks of gestation are displayed in Table 4.

Table 4 Proportion of Subjects Delivering at <37, <35 and <32 Weeks Gestational Age (ITT Population)
1Four Makena-treated subjects were lost to follow-up. They were counted as deliveries at their gestational ages at time of last contact (184, 220, 343 and 364 weeks). 2Adjusted for interim analysis.
Delivery Outcome	Makena1 (N=310) %	Control (N=153) %	Treatment difference and 95% Confidence Interval2
<37 weeks	37.1	54.9	-17.8% [-28.0%, -7.4%]
<35 weeks	21.3	30.7	-9.4% [-19.0%, -0.4%]
<32 weeks	11.9	19.6	-7.7% [-16.1%, -0.3%]

Compared to controls, treatment with Makena reduced the proportion of women who delivered preterm at <37 weeks. The proportions of women delivering at <35 and < 32 weeks also were lower among women treated with Makena. The upper bounds of the confidence intervals for the treatment difference at < 35 and <32 weeks were close to zero. Inclusion of zero in a confidence interval would indicate the treatment difference is not statistically significant. Compared to the other gestational ages evaluated, the number of preterm births at <32 weeks was limited.

After adjusting for time in the study, 7.5% of Makena-treated subjects delivered prior to 25 weeks compared to 4.7% of control subjects; see Figure 1.

Figure 1 Proportion of Women Remaining Pregnant as a Function of Gestational Age

The rates of fetal and neonatal deaths in each treatment arm are displayed in Table 5. Due to the higher rate of miscarriages and stillbirths in the Makena arm, there was no overall survival difference demonstrated in this clinical trial.

Table 5 Fetal Losses and Neonatal Deaths
AFour of the 310 Makena-treated subjects were lost to follow-up and stillbirth or neonatal status could not be determined BPercentages are based on the number of enrolled subjects and not adjusted for time on drug CPercentage adjusted for the number of at risk subjects (n=209 for Makena, n=107 for control) enrolled at <20 weeks gestation.
Complication	Makena N=306A n (%)B	Control N=153 n (%)B
Miscarriages <20 weeks gestationC	5 (2.4)	0
Stillbirth	6 (2.0)	2 (1.3)
Antepartum stillbirth	5 (1.6)	1 (0.6)
Intrapartum stillbirth	1 (0.3)	1 (0.6)
Neonatal deaths	8 (2.6)	9 (5.9)
Total Deaths	19 (6.2)	11 (7.2)

A composite neonatal morbidity/mortality index evaluated adverse outcomes in livebirths. It was based on the number of neonates who died or experienced respiratory distress syndrome, bronchopulmonary dysplasia, grade 3 or 4 intraventricular hemorrhage, proven sepsis, or necrotizing enterocolitis. Although the proportion of neonates who experienced 1 or more events was numerically lower in the Makena arm (11.9% vs. 17.2%), the number of adverse outcomes was limited and the difference between arms was not statistically significant.

Infant Follow-Up Safety Study

Infants born to women enrolled in this study, and who survived to be discharged from the nursery, were eligible for participation in a follow-up safety study. Of 348 eligible offspring, 79.9% enrolled: 194 children of Makena-treated women and 84 children of control subjects. The primary endpoint was the score on the Ages & Stages Questionnaire (ASQ), which evaluates communication, gross motor, fine motor, problem solving, and personal/social parameters. The proportion of children whose scores met the screening threshold for developmental delay in each developmental domain was similar for each treatment group.2

REFERENCES

1Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348(24):2379-85.

2Northen A, Norman G, Anderson K, et al. Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate. Obstet & Gynecol. 2007;110:865-872.

How Supplied/Storage and Handling

Makena (NDC 64011-243-01) is supplied as 5 mL of a sterile solution in a multidose glass vial.

Each 5 mL vial contains hydroxyprogesterone caproate USP, 250 mg/mL (25% w/v), in castor oil USP (28.6% v/v) and benzyl benzoate USP (46% v/v) with the preservative benzyl alcohol NF (2% v/v).

Single unit carton: Contains one 5 mL multidose vial of Makena (250 mg/mL) containing 1250 mg of hydroxyprogesterone caproate.

Store at controlled room temperature [15°-30°C (59°-86°F)]. Use within 5 weeks after first use.

Caution: Protect vial from light. Store vial in its box. Store upright.

Patient Counseling Information

See FDA-approved patient labeling (Patient Information).

Counsel patients that Makena injections may cause pain, soreness, swelling, itching or bruising. Inform the patient to contact her physician if she notices increased discomfort over time, oozing of blood or fluid, or inflammatory reactions at the injection site [see Adverse Reactions (6.1)] .

Patient Information

Makena (mah-KEE-na)

(hydroxyprogesterone caproate injection) 250 mg/mL

Read this Patient Information Leaflet before you receive Makena. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is Makena?

Makena is a prescription hormone medicine (progestin) used in women who are pregnant and who have delivered a baby too early (preterm) in the past. Makena is used in these women to help lower the risk of having a preterm baby again.

Makena is for women who:

• Are pregnant with one baby


• Have had a preterm delivery of one baby in the past

How well does Makena work?

Makena was studied in women who were at risk for having a preterm baby because they had previously given birth to a preterm baby. In the main study, about 37 of 100 women who received Makena gave birth preterm (before 37 weeks of pregnancy), compared to about 55 of 100 women who did not receive Makena. Another study of Makena is going on to see whether Makena reduces the number of babies who have serious problems shortly after birth or who die.

It is not known whether Makena is safe and effective in women who have other risk factors for preterm birth.

It is not known whether Makena is safe and effective in women less than 16 years old.

Makena is not intended for use to stop active preterm labor.

Who should not receive Makena?

Makena should not be used if you:

• Have now or have had a history of blood clots or other blood clotting problems


• Have now or have had a history of breast cancer or other hormone-sensitive cancers


• Have unusual vaginal bleeding not related to your current pregnancy


• Have yellowing of your skin due to liver problems during your pregnancy


• Have liver problems, including liver tumors


• Have uncontrolled high blood pressure

What should I tell my healthcare provider before receiving Makena?

Before you receive Makena, tell your healthcare provider if you have:

• An allergy to hydroxyprogesterone caproate, castor oil, or any of the other ingredients in Makena. See the end of this patient leaflet for a complete list of the ingredients in Makena.


• Diabetes or prediabetes


• Epilepsy


• Migraine headaches


• Asthma


• Heart problems


• Kidney problems


• Depression


• High blood pressure

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Makena may affect the way other medicines work, and other medicines may affect how Makena works.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medication.

How should I receive Makena?

• Do not give yourself Makena injections. A healthcare professional will give you the Makena injection into your hip area (upper outer area of the buttocks) once a week (every 7 days).


• You will start receiving Makena injections anytime from 16 weeks and 0 days of your pregnancy up to 20 weeks and 6 days of your pregnancy.


• You will continue to receive Makena injections once weekly until week 37 of your pregnancy or when your baby is delivered, whichever happens first.

Makena comes in ready-to-use vials. There are 5 doses of medicine in each vial. Your healthcare professional should give you only one dose (1 mL) of Makena as prescribed each week.

Makena should be used within 5 weeks after the first use.

It is very important that you do not miss a dose of Makena and that you continue to receive the medicine once a week. If you miss a dose, talk to your healthcare provider for specific directions on how to get back on schedule.

What are the possible side effects of Makena?

Makena may cause serious side effects, including:

• Blood clots. Symptoms of a blood clot may include:

 

• Leg swelling


• Redness in your leg


• A spot on your leg that is warm to touch


• Leg pain that worsens when you bend your foot

• Allergic reactions. Symptoms of an allergic reaction may include:

 

• Hives


• Itching


• Swelling of the face

Call your healthcare provider right away if you get any of the symptoms above. 

• Depression


• Yellowing of your skin and the whites of your eyes

The most common side effects of Makena include:

• Pain, swelling, itching, bruising or a hard bump at the injection site


• Hives


• Itching


• Nausea


• Diarrhea

Call your healthcare provider if you have the following at your injection site:

• Increased pain over time


• Oozing of blood or fluid


• Swelling

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Makena. For more information, ask your healthcare provider or pharmacist.

In a clinical study, certain complications or events associated with pregnancy occurred more often in women who received Makena compared to women who did not receive Makena, including:

• Miscarriage (pregnancy loss before 20 weeks of pregnancy)


• Stillbirth (fetal death occurring after the 20th week of pregnancy)


• Hospital admission for preterm labor


• Preeclampsia (high blood pressure and too much protein in your urine)


• Gestational hypertension (high blood pressure caused by pregnancy)


• Gestational diabetes


• Oligohydramnios (low amniotic fluid levels)

Call your healthcare provider for medical advice about side effects or pregnancy complications. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Makena?

• Store Makena at room temperature (59° to 86°F or 15° to 30°C)


• Store Makena in the original box to protect it from light


• Store the Makena box upright


• Makena should be used within 5 weeks after first use.


• Keep Makena out of the reach of children

General information about the safe and effective use of Makena.

Medicines are sometimes prescribed for purposes other than those mentioned in the Patient Information Leaflets. Do not take Makena for conditions for which it was not prescribed. Do not give Makena to other people, even if they have the same condition you have. It may harm them.

This leaflet summarizes the most important information about Makena. If you would like more information, talk with your healthcare provider. You can ask for information about Makena that is written for healthcare professionals.

For more information, go to www.Makena.com or call Ther-Rx Corporation Customer Service at the toll free number 1-877-567-7676.

To refill a prescription or to check on prescription status, call the Makena Care Connection at the toll free number 1-800-847-3418.

What are the ingredients in Makena?

Active ingredient: hydroxyprogesterone caproate

Inactive ingredients: castor oil, benzyl benzoate, and benzyl alcohol (a preservative)

Manufactured by:

Baxter Pharmaceutical Solutions LLC

Bloomington, IN 47403

Marketed by:

Ther-Rx Corporation

St. Louis, MO 63044

P10059-1

3-1214-303

2/2011

PRINCIPAL DISPLAY PANEL

NDC 64011-243-01

MakenaTM

hydroxyprogesterone caproate injection

1250 mg/5 mL

(250 mg/mL)

FOR INTRAMUSCULAR USE

5 mL multidose vial

Rx ONLY

Makena  hydroxyprogesterone caproate  injection

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 64011-243 Route of Administration INTRAMUSCULAR DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Hydroxyprogesterone Caproate (Hydroxyprogesterone Caproate) Hydroxyprogesterone Caproate 250 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength CASTOR OIL 277.8 mg  in 1 mL BENZYL BENZOATE 514.3 mg  in 1 mL BENZYL ALCOHOL 21.92 mg  in 1 mL

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 64011-243-01 5 mL In 1 VIAL, GLASS None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA021945	02/03/2011

Labeler - Ther-Rx Corporation (055041706)

Registrant - KV Pharmaceutical Co. (006291405)

Establishment
Name	Address	ID/FEI	Operations
Baxter Pharmaceutical Solutions, LLC		604719430	manufacture, analysis

Revised: 02/2011Ther-Rx Corporation

More Makena resources

• Makena Side Effects (in more detail)
• Makena Use in Pregnancy & Breastfeeding
• Makena Drug Interactions
• Makena Support Group
• 0 Reviews for Makena - Add your own review/rating

• Makena Advanced Consumer (Micromedex) - Includes Dosage Information


• Makena MedFacts Consumer Leaflet (Wolters Kluwer)


• Makena Consumer Overview

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• Premature Labor

Namenda Solution

Pronunciation: me-MAN-teen
Generic Name: Memantine
Brand Name: Namenda

Namenda Solution is used for:

Treating moderate to severe Alzheimer-type dementia. It may also be used for other conditions as determined by your doctor.

Namenda Solution is an N-methyl-D-aspartate (NMDA)-receptor antagonist. It works by blocking excess activity of a substance in the brain called glutamate, which may reduce the symptoms associated with Alzheimer disease. Namenda Solution is not a cure for Alzheimer disease.

Do NOT use Namenda Solution if:

• you are allergic to any ingredient in Namenda Solution

Contact your doctor or health care provider right away if any of these apply to you.

Before using Namenda Solution:

Some medical conditions may interact with Namenda Solution. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have liver problems, kidney problems, seizures, or a condition that raises your urine pH balance (eg, urinary tract infection)

Some MEDICINES MAY INTERACT with Namenda Solution. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Amantadine, carbonic anhydrase inhibitors (eg, acetazolamide), dextromethorphan, ketamine, or sodium bicarbonate because they may increase the risk of Namenda Solution's side effects

This may not be a complete list of all interactions that may occur. Ask your health care provider if Namenda Solution may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Namenda Solution:

Use Namenda Solution as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Namenda Solution. Talk to your pharmacist if you have questions about this information.


• Take Namenda Solution by mouth with or without food. If stomach upset occurs, take with food to reduce stomach irritation.


• Use the measuring device marked for medicine dosing that came with Namenda Solution. Ask your pharmacist for help if you are unsure of how to measure your dose.


• If you miss a dose of Namenda Solution, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Namenda Solution.

Important safety information:

• Namenda Solution may cause dizziness or drowsiness. These effects may be worse if you take it with alcohol or certain medicines. Use Namenda Solution with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do NOT take more than the recommended dose without checking with your doctor.


• Namenda Solution should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Namenda Solution while you are pregnant. It is not known if Namenda Solution is found in breast milk. If you are or will be breast-feeding while you use Namenda Solution, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Namenda Solution:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Back pain; constipation; diarrhea; dizziness; drowsiness; headache; pain; weight gain.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); change in behavior, such as aggressiveness, depression, or anxiety; chest pain or tightness; fainting; hallucinations; one-sided weakness; seizures; severe tiredness; speech changes; sudden, severe headache; vision changes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Namenda side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include confusion; loss of consciousness; mental or mood changes; restlessness; seeing things that are not there (hallucinations); severe drowsiness or dizziness; slow heartbeat; sluggishness; unsteadiness; unusual tiredness or weakness.

Proper storage of Namenda Solution:

Store Namenda Solution at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Namenda Solution out of the reach of children and away from pets.

General information:

• If you have any questions about Namenda Solution, please talk with your doctor, pharmacist, or other health care provider.


• Namenda Solution is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Namenda Solution. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Namenda resources

• Namenda Side Effects (in more detail)
• Namenda Dosage
• Namenda Use in Pregnancy & Breastfeeding
• Drug Images
• Namenda Drug Interactions
• Namenda Support Group
• 9 Reviews for Namenda - Add your own review/rating

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• Alzheimer's Disease

emtricitabine, nelfinavir, and tenofovir

Generic Name: emtricitabine, nelfinavir, and tenofovir (em trye SYE ta been, nel FIN a veer, ten OF oh vir)

Brand Names: AccessPak for HIV PEP Expanded with Viracept

What is emtricitabine, nelfinavir, and tenofovir?

Emtricitabine, nelfinavir, and tenofovir are antiviral drugs that prevent HIV (human immunodeficiency virus) cells from multiplying in your body.

The combination of emtricitabine, nelfinavir, and tenofovir is used to treat HIV, which causes acquired immunodeficiency syndrome (AIDS). This medication is not a cure for HIV or AIDS.

Emtricitabine, nelfinavir, and tenofovir may also be used for purposes not listed in this medication guide.

What is the most important information I should know about emtricitabine, nelfinavir, and tenofovir?

You should not take this medication if you have severe liver or kidney disease, or if you are allergic to emtricitabine (Emtriva, Atripla), nelfinavir (Viracept), or tenofovir (Viread). Do not take this medication with other medicines that also contain emtricitabine or tenofovir (Atripla, Emtriva, Viread), or lamivudine (Combivir, Epivir, Epzicom, or Trizivir).

There are many other drugs that can cause serious or life threatening medical problems if you take them together with this medication. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

Some people develop lactic acidosis while taking emtricitabine or tenofovir. Early symptoms may get worse over time and this condition can be fatal. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, slow or uneven heart rate, dizziness, or feeling very weak or tired.

What should I discuss with my healthcare provider before taking emtricitabine, nelfinavir, and tenofovir?

You should not take this medication if you have severe liver or kidney disease, or if you are allergic to emtricitabine (Emtriva, Atripla), nelfinavir (Viracept), or tenofovir (Viread). Do not take this medication with other medicines that also contain emtricitabine or tenofovir (Atripla, Emtriva, Viread), or lamivudine (Combivir, Epivir, Epzicom, or Trizivir).

There are many other drugs that can cause serious or life threatening medical problems if you take them together with emtricitabine, nelfinavir, and tenofovir. The following drugs should not be used while you are taking this medication:

• 
  

  amiodarone (Cordarone, Pacerone);

  
  


• 
  

  quinidine (Quin-G);

  
  


• 
  

  pimozide (Orap);

  
  


• 
  

  midazolam (Versed) or triazolam (Halcion); or

  
  


• 
  

  an ergot medicine such as D.H.E. 45, Ergomar, Cafergot, Ergotrate, Methergine, Migergot, or Migranal.

  
  

To make sure you can safely take emtricitabine, nelfinavir, and tenofovir, tell your doctor if you have any of these other conditions:

• 
  

  diabetes;

  
  


• 
  

  a bleeding or blood-clotting disorder such as hemophilia;

  
  


• 
  

  high cholesterol or triglycerides (a type of fat in the blood);

  
  


• liver or kidney disease;


• 
  

  osteopenia (low bone mineral density); or

  
  


• 
  

  if you also have hepatitis B infection.

  
  

Some people develop a life-threatening condition called lactic acidosis while taking emtricitabine or tenofovir. You may be more likely to develop lactic acidosis if you are overweight or have liver disease, if you are a woman, or if you have taken HIV or AIDS medications for a long time. Talk with your doctor about your individual risk. FDA pregnancy category B. Tell your doctor if you are pregnant or plan to become pregnant during treatment. HIV can be passed to your baby if you are not properly treated during pregnancy. Take all of your HIV medicines as directed to control your infection. Women with HIV or AIDS should not breast-feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk. Do not give this medicine to a child younger than 2 years old without medical advice.

How should I take emtricitabine, nelfinavir, and tenofovir?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

This medicine works best if you take it with food.

To be sure this medication is helping your condition and not causing harmful effects, your blood will need to be tested often. Your kidney and liver function or bone density may also need to be tested. Visit your doctor regularly.

If you have hepatitis B you may develop liver symptoms after you stop taking emtricitabine, nelfinavir, and tenofovir, even months after stopping. Your doctor may want to check your liver function at regular visits for several months after you stop using the medicine. Do not miss any follow-up visits to your doctor.

HIV/AIDS is usually treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice. Every person with HIV or AIDS should remain under the care of a doctor.

Store at room temperature away from moisture and heat. Keep the tablets in their original container, along with the packet of moisture-absorbing preservative that comes with this medicine.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking emtricitabine, nelfinavir, and tenofovir?

If you also take didanosine, take it 1 hour before or 2 hours after you take emtricitabine, nelfinavir, and tenofovir.

Taking this medication will not prevent you from passing HIV to other people. Avoid having unprotected sex or sharing razors or toothbrushes. Talk with your doctor about safe ways to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Emtricitabine, nelfinavir, and tenofovir side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. This medication may cause lactic acidosis (a build-up of lactic acid in the body, which can be fatal). Lactic acidosis can start slowly and get worse over time. Get emergency medical help if you have even mild symptoms of lactic acidosis, such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, slow or uneven heart rate, dizziness, or feeling very weak or tired. Call your doctor at once if you have a serious side effect such as:

• 
  

  nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

  
  


• 
  

  increased thirst, urinating less than usual or not at all;

  
  


• 
  

  easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

  
  


• 
  

  swelling, rapid weight gain, feeling short of breath; or

  
  


• 
  

  signs of infection such as fever, chills, skin lesions, or cough with yellow or green mucus.

  
  

Less serious side effects may include:

• 
  

  vomiting, diarrhea, bloating;

  
  


• 
  

  headache, tired feeling, dizziness, depressed mood;

  
  


• 
  

  sleep problems (insomnia), strange dreams;

  
  


• 
  

  runny or stuffy nose, cough; or

  
  


• 
  

  changes in the shape or location of body fat (especially in your arms, legs, face, neck, breasts, and waist).

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect emtricitabine, nelfinavir, and tenofovir?

Emtricitabine, nelfinavir, and tenofovir can harm your kidneys. This effect is increased when you also use other medicines harmful to the kidneys. You may need dose adjustments or special tests if you have recently used:

• 
  

  lithium (Lithobid);

  
  


• 
  

  methotrexate (Rheumatrex, Trexall);

  
  


• 
  

  pain or arthritis medicines such as aspirin (Anacin, Excedrin), acetaminophen (Tylenol), ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Voltaren), indomethacin (Indocin), meloxicam (Mobic), and others;

  
  


• 
  

  medicines used to prevent organ transplant rejection, such as cyclosporine (Gengraf, Neoral, Sandimmune), sirolimus (Rapamune) or tacrolimus (Prograf);

  
  


• 
  

  IV antibiotics such as amphotericin B (Fungizone, AmBisome, Amphotec, Abelcet), amikacin (Amikin), bacitracin (Baci IM), capreomycin (Capastat), gentamicin (Garamycin), kanamycin (Kantrex), streptomycin, or vancomycin (Vancocin, Vancoled);

  
  


• 
  

  antiviral medicines such as adefovir (Hepsera), cidofovir (Vistide), or foscarnet (Foscavir); or

  
  


• 
  

  cancer medicine such as aldesleukin (Proleukin), carmustine (BiCNU, Gliadel), cisplatin (Platinol), ifosfamide (Ifex), oxaliplatin (Eloxatin), streptozocin (Zanosar), or tretinoin (Vesanoid).

  
  

You may need dose adjustments or special tests when taking any of these medications together with emtricitabine, nelfinavir, and tenofovir.

Many other drugs can interact with emtricitabine, nelfinavir, and tenofovir. Below is just a partial list:

• 
  

  antiviral medications for herpes or HIV;

  
  


• 
  

  antifungal medicine;

  
  


• 
  

  cholesterol-lowering medicines;

  
  


• 
  

  heart or blood pressure medications;

  
  


• 
  

  insulin or oral diabetes medication;

  
  


• 
  

  seizure medications; or

  
  


• 
  

  medicines to treat erectile dysfunction.

  
  

This list is not complete and other drugs may interact with emtricitabine, nelfinavir, and tenofovir. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More emtricitabine, nelfinavir, and tenofovir resources

• Emtricitabine, nelfinavir, and tenofovir Drug Interactions
• Emtricitabine, nelfinavir, and tenofovir Support Group
• 0 Reviews for Emtricitabine, nelfinavir, and tenofovir - Add your own review/rating

Compare emtricitabine, nelfinavir, and tenofovir with other medications

• HIV Infection

Where can I get more information?

• Your pharmacist can provide more information about emtricitabine, nelfinavir, and tenofovir.

Loxitane C

Generic Name: loxapine (LOX a peen)

Brand Names: Loxitane

What is Loxitane C (loxapine)?

Loxapine is an antipsychotic medication. It affects the actions of chemicals in your brain.

Loxapine is used to treat schizophrenia.

Loxapine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Loxitane C (loxapine)?

Loxapine is not for use in psychotic conditions related to dementia. Loxapine may cause heart failure, sudden death, or pneumonia in older adults with dementia-related conditions.

You should not use this medication if you are allergic to loxapine, or if you have decreased alertness caused by taking certain medications or drinking alcohol.

Call your doctor at once if you have restless muscle movements in your eyes, tongue, jaw, or neck.

Loxapine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Avoid drinking alcohol. You should not take loxapine if you are under the effects of alcohol.

Avoid becoming overheated or dehydrated during exercise and in hot weather. Loxapine can decrease perspiration and you may be more prone to heat stroke.

What should I discuss with my healthcare provider before taking Loxitane C (loxapine)?

Loxapine is not for use in psychotic conditions related to dementia. Loxapine may cause heart failure, sudden death, or pneumonia in older adults with dementia-related conditions. You should not use this medication if you are allergic to loxapine, or if you have decreased alertness caused by taking certain medications or drinking alcohol.

To make sure you can safely take loxapine, tell your doctor if you have any of these other conditions:

• 
  

  epilepsy or other seizure disorder;

  
  


• 
  

  a history of low white blood cell (WBC) counts;

  
  


• 
  

  glaucoma;

  
  


• 
  

  urination problems;

  
  


• 
  

  heart disease; or

  
  


• 
  

  a history of breast cancer;

  
  

Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Taking antipsychotic medication during the last 3 months of pregnancy may cause problems in the newborn, such as withdrawal symptoms, breathing problems, feeding problems, fussiness, tremors, and limp or stiff muscles. However, you may have withdrawal symptoms or other problems if you stop taking your medicine during pregnancy. If you become pregnant while taking loxapine, do not stop taking it without your doctor's advice. It is not known whether loxapine passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take Loxitane C (loxapine)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Your doctor may occasionally change your dose to make sure you get the best results.

Loxapine is usually taken 2 to 4 times daily. Follow your doctor's instructions.

Take loxapine with a full glass of water. You may not start feeling better right away when you start taking loxapine. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve during treatment. Store at room temperature away from moisture, heat, and light.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include drowsiness, dizziness, muscle stiffness or twitching, increased salivation, trouble swallowing, weakness, loss of balance or coordination, weak pulse, slow heart rate, weak or shallow breathing, fainting, or seizure (convulsions).

What should I avoid while taking Loxitane C (loxapine)?

Loxapine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Avoid drinking alcohol. You should not take loxapine if you are under the effects of alcohol.

Avoid becoming overheated or dehydrated during exercise and in hot weather. Loxapine can decrease perspiration and you may be more prone to heat stroke.

Loxitane C (loxapine) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using loxapine and call your doctor at once if you have a serious side effect such as:

• 
  

  very stiff (rigid) muscles, high fever, sweating, confusion, fast or uneven heartbeats, feeling like you might pass out;

  
  


• 
  

  restless muscle movements in your eyes, tongue, jaw, or neck;

  
  


• 
  

  tremor (uncontrolled shaking);

  
  


• 
  

  trouble swallowing;

  
  


• 
  

  seizure (convulsions);

  
  


• 
  

  easy bruising or bleeding, unusual weakness;

  
  


• 
  

  fever, chills, body aches, flu symptoms;

  
  


• 
  

  vision changes;

  
  


• 
  

  severe constipation; or

  
  


• 
  

  urinating less than usual or not at all.

  
  

Less serious side effects may include:

• 
  

  dizziness or drowsiness;

  
  


• 
  

  blurred vision;

  
  


• 
  

  puffiness in your face;

  
  


• 
  

  feeling restless or agitated;

  
  


• 
  

  sleep problems (insomnia);

  
  


• 
  

  breast swelling or discharge;

  
  


• 
  

  changes in your menstrual periods;

  
  


• 
  

  nausea, vomiting, constipation;

  
  


• 
  

  changes in weight;

  
  


• 
  

  dry mouth, stuffy nose; or

  
  


• 
  

  mild skin rash, itching, or flaking.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Loxitane C (loxapine)?

Before using loxapine, tell your doctor if you regularly use other medicines that make you sleepy (such as cold or allergy medicine, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). You should not take loxapine if you have drowsiness caused by other medications.

Tell your doctor about all other medications you use, especially:

• 
  

  atropine (Atreza, Sal-Tropine), belladonna (Donnatal, and others), benztropine (Cogentin), dimenhydrinate (Dramamine), methscopolamine (Pamine), or scopolamine (Transderm-Scop);

  
  


• 
  

  bronchodilators such as ipratropium (Atrovent) or tiotropium (Spiriva);

  
  


• 
  

  glycopyrrolate (Robinul);

  
  


• 
  

  mepenzolate (Cantil);

  
  


• 
  

  bladder or urinary medications such as darifenacin (Enablex), flavoxate (Urispas), oxybutynin (Ditropan, Oxytrol), tolterodine (Detrol), or solifenacin (Vesicare); or

  
  


• 
  

  irritable bowel medications such as dicyclomine (Bentyl), hyoscyamine (Anaspaz, Cystospaz, Levsin, and others), or propantheline (Pro-Banthine).

  
  

This list is not complete and other drugs may interact with loxapine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Loxitane C resources

• Loxitane C Side Effects (in more detail)
• Loxitane C Use in Pregnancy & Breastfeeding
• Loxitane C Drug Interactions
• Loxitane C Support Group
• 0 Reviews for Loxitane C - Add your own review/rating

• Loxapine Professional Patient Advice (Wolters Kluwer)


• Loxapine MedFacts Consumer Leaflet (Wolters Kluwer)


• loxapine Advanced Consumer (Micromedex) - Includes Dosage Information


• Loxapine Prescribing Information (FDA)


• Loxapine Succinate Monograph (AHFS DI)


• Loxitane Prescribing Information (FDA)

Compare Loxitane C with other medications

• Schizophrenia

Where can I get more information?

• Your pharmacist can provide more information about loxapine.

See also: Loxitane C side effects (in more detail)

Novo-Lexin

Generic Name: cephalexin (Oral route)

sef-a-LEX-in

Commonly used brand name(s)

In the U.S.

• Bio-Cef


• Keflex


• Panixine DisperDose

In Canada

• Novo-Lexin

Available Dosage Forms:

• Tablet


• Capsule


• Tablet for Suspension


• Powder for Suspension

Therapeutic Class: Antibiotic

Pharmacologic Class: 1st Generation Cephalosporin

Uses For Novo-Lexin

Cephalexin is used to treat bacterial infections in many different parts of the body. It belongs to the class of medicines known as cephalosporin antibiotics. It works by killing bacteria or preventing their growth. However, this medicine will not work for colds, flu, or other virus infections.

This medicine is available only with your doctor's prescription.

Before Using Novo-Lexin

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of cephalexin in children.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of cephalexin in the elderly. However, elderly patients are more likely to have age-related kidney problems, which may require caution and an adjustment in the dose for patients receiving cephalexin.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Cholestyramine


• Metformin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Colitis (inflammation in gut), history of or


• Diarrhea, severe, history of—Use with caution. May make these conditions worse.

• Kidney disease—Use with caution. Effects may be increased because of slower removal of the medicine from the body.

Proper Use of cephalexin

This section provides information on the proper use of a number of products that contain cephalexin. It may not be specific to Novo-Lexin. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

Shake the oral liquid well before each use. Measure the medicine with a marked measuring spoon, oral syringe, or medicine cup. The average household teaspoon may not hold the right amount of liquid.

Keep using this medicine for the full treatment time, even if you feel better after the first few doses. Your infection may not clear up if you stop using the medicine too soon.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage forms (capsules or suspension):
  
  • For infections:
    
    • Adults and teenagers—The dose is 1000 to 4000 milligrams (mg) per day, taken in divided doses.
    
    
    • Children—Use and dose must be determined by your doctor. Dose is based on body weight and must be determined by your doctor. The dose is usually 25 to 100 milligrams (mg) per kilogram (kg) per day, taken in divided doses.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the capsules in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Store the oral liquid in the refrigerator. Throw away any unused medicine after 14 days.

Precautions While Using Novo-Lexin

If your symptoms do not improve within a few days, or if they become worse, check with your doctor.

Cephalexin may cause diarrhea, and in some cases it can be severe. Do not take any medicine or give medicine to your child to treat diarrhea without first checking with your doctor. Diarrhea medicines may make the diarrhea worse or make it last longer. If you have any questions about this or if mild diarrhea continues or gets worse, check with your doctor.

Before you or your child have any medical tests, tell the medical doctor in charge that you are using this medicine. The results of some tests may be affected by this medicine.

Novo-Lexin Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Diarrhea

Rare

• Abdominal or stomach pain


• blistering, peeling, or loosening of the skin


• chills


• clay-colored stools


• cough


• dark urine


• diarrhea


• dizziness


• fever


• general tiredness and weakness


• headache


• itching


• joint or muscle pain


• light-colored stools


• loss of appetite


• nausea and vomiting


• rash


• red skin lesions, often with a purple center


• red, irritated eyes


• sore throat


• sores, ulcers, or white spots in the mouth or on the lips


• unpleasant breath odor


• unusual tiredness or weakness


• upper right abdominal or stomach pain


• vomiting of blood


• yellow eyes or skin

Incidence not known

• Abdominal or stomach cramps or tenderness


• back or leg pains


• black, tarry stools


• bleeding gums


• bloating


• blood in the urine or stools


• chest pain


• coughing up blood


• diarrhea, watery and severe, which may also be bloody


• difficulty with breathing or swallowing


• fast heartbeat


• general body swelling


• hives


• increased menstrual flow or vaginal bleeding


• increased thirst


• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs


• loss of appetite


• nosebleeds


• pain


• painful or difficult urination


• pale skin


• paralysis


• pinpoint red spots on the skin


• prolonged bleeding from cuts


• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue


• red or black, tarry stools


• red or dark brown urine


• shortness of breath


• swollen or painful glands


• tightness in the chest


• unusual bleeding or bruising


• unusual weight loss


• watery or bloody diarrhea


• wheezing

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Incidence not known

• Acid or sour stomach


• anxiety


• belching


• burning feeling in the chest or stomach


• difficulty with moving


• dry mouth


• heartburn


• hives or welts


• hyperventilation


• indigestion


• irregular heartbeats


• irritability


• itching of the vagina or genital area


• muscle pain or stiffness


• nervousness


• pain during sexual intercourse


• pain, swelling, or redness in the joints


• redness of the skin


• restlessness


• seeing, hearing, or feeling things that are not there


• shaking


• stomach upset


• trouble with sleeping


• white or brownish vaginal discharge

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Novo-Lexin side effects (in more detail)

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More Novo-Lexin resources

• Novo-Lexin Side Effects (in more detail)
• Novo-Lexin Use in Pregnancy & Breastfeeding
• Drug Images
• Novo-Lexin Drug Interactions
• Novo-Lexin Support Group
• 57 Reviews for Novo-Lexin - Add your own review/rating

Compare Novo-Lexin with other medications

• Acne
• Bacterial Endocarditis Prevention
• Bacterial Infection
• Bladder Infection
• Bone infection
• Kidney Infections
• Otitis Media
• Pharyngitis
• Prostatitis
• Skin Infection
• Upper Respiratory Tract Infection