This combination tablet is indicated for the treatment of heart failure as an adjunct to standard therapy in self-identified black patients to improve survival, to prolong time to hospitalization for heart failure, and to improve patient-reported functional status.

Limitations of use: There is little experience in patients with NYHA class IV heart failure.

Each coated tablet contains:

• Diluted Isosorbide Dinitrate USP 80 mg equivalent to Isosorbide Dinitrate 20 mg
• Hydralazine Hydrochloride 37.5 mg

The mechanism of action underlying the beneficial effects in the treatment of heart failure has not been established. Isosorbide dinitrate is a vasodilator affecting both arteries and veins. Its dilator properties result from the release of nitric oxide and the subsequent activation of guanylyl cyclase, and ultimate relaxation of vascular smooth muscle. Several well-controlled clinical trials have used exercise testing to assess the anti-anginal efficacy of chronically delivered nitrates. In the large majority of these trials, active agents were no more effective than placebo after 24 hours (or less) of continuous therapy. Attempts to overcome nitrate tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates have been absent from the body for several hours is the response to nitrates restored. Hydralazine hydrochloride is a selective dilator of arterial smooth muscle. Animal data suggests that hydralazine may also mitigate tolerance to nitrates.

Route of administration: Isozine should be taken in oral route.

This tablet should be initiated at a dose of one tablet, three times a day. Dosing should be titrated to a maximum of two tablets three times daily, if tolerated. Although titration of this tablet can be rapid (3-5 days), some patients may experience side effects and may take longer to reach their maximum tolerated dose. The dosage may be decreased to as one-half of this tablet three times a day, if intolerable side effects occur. Efforts should be made to titrate up as soon as side effects subside.

Use in children and adolescents: The safety and effectiveness of this combination in children have not been established.

Drug interaction with medication: This combination is contraindicated in patients who are using a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). PDE5 inhibitors such as avanafil, sildenafil, vardenafil and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates. This combination is not to be used in patients who are taking the soluble guanylate cyclase (sGC) stimulator riociguat. Concomitant use can cause hypotension

This combination is contraindicated in patients with known hypersensitivity to isosorbide dinitrate or hydralazine hydrochloride or organic nitrates or any other components of this product. It is also contraindicated in patients who are taking PDE-5 inhibitors or the soluble guanylate cyclase (sGC) stimulator riociguat.

The following adverse reactions have been identified during post-approval use of this tablet:

• Cardiac Disorders: Palpitations
• Ear and Labyrinth Disorders: Tinnitus, vertigo
• Eye Disorders: Eyelid edema, blurred vision
• Gastrointestinal Disorders: Abdominal discomfort, constipation
• General Disorders and Administration Site Conditions: Facial pain, flushing, chest discomfort, chest pain, peripheral edema
• Musculoskeletal and Connective Tissue Disorders: Pain in extremity, myalgia
• Nervous Disorders: Dysgeusia, hypoaesthesia, migraine, syncope
• Renal and Urinary Disorders: Chromaturia, pulmonary renal syndrome
• Respiratory, Thoracic and Mediastinal Disorders: Dyspnea
• Reproductive System and Breast Disorders: Erectile dysfunction
• Skin and Subcutaneous Tissue Disorders: Erythema, hyperhidrosis, pruritus, face swelling

Pregnancy: There are no data on this combination's use in pregnant women and insufficient data on its components to assess a drug-associated risk of major birth defects or miscarriage with first-trimester use. Available published data on hydralazine use in pregnancy during the second and third trimesters have not shown an association with adverse pregnancy-related outcomes.

Lactation: The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for this combination and any potential adverse effects on the breastfed child from this combination or from the underlying maternal condition.

Symptomatic hypotension, particularly with upright posture, may occur with even small doses of this combination. Hypotension is most likely to occur in patients who have been volume or salt depleted; it should be corrected prior to administration. Hydralazine hydrochloride has been reported to cause a drug-induced systemic lupus erythematosus (SLE) syndrome. Symptoms and signs usually regress when hydralazine hydrochloride is discontinued. Hydralazine hydrochloride can cause tachycardia and hypotension, potentially leading to myocardial ischemia and angina, particularly in patients with hypertrophic cardiomyopathy. Hydralazine hydrochloride has been associated with peripheral neuritis, evidenced by paresthesia, numbness and tingling, which may be related to an antipyridoxine effect. Pyridoxine should be added to this combination therapy if such symptoms develop.

Geriatric Use: Clinical studies of this tablet did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between elderly and younger patients. In general, dose selection for an elderly patient should start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic and renal function, and of concomitant disease or other drug therapies. Isosorbide dinitrate, its active metabolites, and hydralazine may be eliminated more slowly in elderly patients.

Renal Impairment: There are no studies of renal impairment using this tablet. No dose adjustment is required for hydralazine or isosorbide dinitrate. The dialyzability of hydralazine has not been determined. Dialysis is not an effective method for removing isosorbide dinitrate or its metabolite isosorbide-5-mononitrate from the body.

Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of hydralazine alone has not been determined. Isosorbide dinitrate concentrations increase in patients with cirrhosis. There are no studies of hepatic impairment using this tablet.

There are no documented cases of overdosage with this combination. No deaths from acute poisoning have been reported. There is no specific antidote. Support of the cardiovascular system is of primary importance. Dialysis is not effective in removing circulating isosorbide dinitrate. The dialyzability of hydralazine has not been determined.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.