Ritonavir (Page 3 of 9)

5.7 Lipid Disorders

Treatment with ritonavir therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total cholesterol and triglycerides [see Adverse Reactions ( 6.1)]. Triglyceride and cholesterol testing should be performed prior to initiating ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with ritonavir and HMG CoA reductase inhibitors [see Contraindications ( 4) and Drug Interactions ( 7)].

5.8 Diabetes Mellitus/Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established. Consider monitoring for hyperglycemia, new onset diabetes mellitus, or an exacerbation of diabetes mellitus in patients treated with ritonavir.

5.9 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including ritonavir. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.10 Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.11 Patients with Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.

5.12 Resistance/Cross-resistance

Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of ritonavir 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors [see Microbiology ( 12.4)].

5.13 Laboratory Tests

Ritonavir has been shown to increase triglycerides, cholesterol, SGOT (AST), SGPT (ALT), GGT, CPK, and uric acid. Appropriate laboratory testing should be performed prior to initiating ritonavir therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling.
• Drug Interactions [see Warnings and Precautions ( 5.1)]
• Hepatotoxicity [see Warnings and Precautions ( 5.3)]
• Pancreatitis [see Warnings and Precautions ( 5.4)]
• Allergic Reactions/Hypersensitivity [see Warnings and Precautions ( 5.5)]
When co-administering ritonavir with other protease inhibitors, see the full prescribing information for that protease inhibitor including adverse reactions.

6.1 Clinical Trial Experience

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

Adverse Reactions in Adults
The safety of ritonavir alone and in combination with other antiretroviral agents was studied in 1,755 adult patients. Table 2 lists treatment-emergent Adverse Reactions (with possible or probable relationship to study drug) occurring in greater than or equal to 1% of adult patients receiving ritonavir in combined Phase II/IV studies.
The most frequently reported adverse drug reactions among patients receiving ritonavir alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia and oral paresthesia), rash, and fatigue/asthenia. Table 2. Treatment-Emergent Adverse Reactions (With Possible or Probable Relationship to Study Drug) Occurring in greater than or equal to 1% of Adult Patients Receiving Ritonavir in Combined Phase II/IV Studies (N = 1,755)

Adverse Reactions	n				%
Eye disorders
Blurred vision	113				6.4
Gastrointestinal disorders
Abdominal Pain (upper and lower)*	464				26.4
Diarrhea including severe with electrolyte imbalance*	1,192				67.9
Dyspepsia	201				11.5
Flatulence	142				8.1
Gastrointestinal hemorrhage*	41				2.3
Gastroesophageal reflux disease (GERD)	19				1.1
Nausea	1,007				57.4
Vomiting*	559				31.9
General disorders and administration site conditions
Fatigue including asthenia*	811				46.2
Hepatobiliary disorders
Blood bilirubin increased (including jaundice)*	25				1.4
Hepatitis (including increased AST, ALT, GGT)*	153				8.7
Immune system disorders
Hypersensitivity including urticaria and face edema*	114				8.2
Metabolism and nutrition disorders
Edema and peripheral edema*			110	6.3
Gout*			24	1.4
Hypercholesterolemia*			52	3
Hypertriglyceridemia*			158	9
Lipodystrophy acquired*			51	2.9
Musculoskeletal and connective tissue disorders
Arthralgia and back pain*		326		18.6
Myopathy/creatine phosphokinase increased*		66		3.8
Myalgia		156		8.9
Nervous system disorders
Dizziness*		274		15.6
Dysgeusia*		285		16.2
Paresthesia (including oral paresthesia)*		889		50.7
Peripheral neuropathy		178		10.1
Syncope*		58		3.3
Psychiatric disorders
Confusion*		52		3
Disturbance in attention		44		2.5
Renal and urinary disorders
Increased urination*		74		4.2
Respiratory, thoracic and mediastinal disorders
Coughing*		380		21.7
Oropharyngeal Pain*		279		15.9
Skin and subcutaneous tissue disorders
Acne*		67		3.8
Pruritus*		214		12.2
Rash (includes erythematous and maculopapular)*		475		27.1
Vascular disorders
Flushing, feeling hot*		232		13.2
Hypertension*		58		3.3
Hypotension including orthostatic hypotension*		30		1.7
Peripheral coldness*		21		1.2
* Represents a medical concept including several similar MedDRA PTs

Laboratory Abnormalities in Adults
Table 3 shows the percentage of adult patients who developed marked laboratory abnormalities. Table 3. Percentage of Adult Patients, by Study and Treatment Group, with Chemistry and Hematology Abnormalities Occurring in greater than 3% of Patients Receiving Ritonavir

		Study 245 Naive Patients			Study 247 Advanced Patients		Study 462 PI-Naive Patients
Variable	Limit	Ritonavir plus ZDV	Ritonavir	ZDV	Ritonavir	Placebo	Ritonavir plus Saquinavir
Chemistry	High
Cholesterol	> 240 mg/dL	30.7	44.8	9.3	36.5	8	65.2
CPK	> 1000 IU/L	9.6	12.1	11	9.1	6.3	9.9
GGT	> 300 IU/L	1.8	5.2	1.7	19.6	11.3	9.2
SGOT (AST)	> 180 IU/L	5.3	9.5	2.5	6.4	7	7.8
SGPT (ALT)	> 215 IU/L	5.3	7.8	3.4	8.5	4.4	9.2
Triglycerides	> 800 mg/dL	9.6	17.2	3.4	33.6	9.4	23.4
Triglycerides	> 1500 mg/dL	1.8	2.6	–	12.6	0.4	11.3
Triglycerides Fasting	> 1500 mg/dL	1.5	1.3	–	9.9	0.3	–
Uric Acid	> 12 mg/dL	–	–	–	3.8	0.2	1.4
Hematology	Low
Hematocrit	< 30%	2.6	–	0.8	17.3	22	0.7
Hemoglobin	< 8 g/dL	0.9	–	–	3.8	3.9	–
Neutrophils	≤ 0.5 x 10 9 /L	–	–	–	6	8.3	–
RBC	< 3 x 10 12 /L	1.8	–	5.9	18.6	24.4	–
WBC	< 2.5 x 10 9 /L	–	0.9	6.8	36.9	59.4	3.5
– Indicates no events reported.

Adverse Reactions in Pediatric Patients
Ritonavir has been studied in 265 pediatric patients greater than 1 month to 21 years of age. The adverse event profile observed during pediatric clinical trials was similar to that for adult patients.
Vomiting, diarrhea, and skin rash/allergy were the only drug-related clinical adverse events of moderate to severe intensity observed in greater than or equal to 2% of pediatric patients enrolled in ritonavir clinical trials.
Laboratory Abnormalities in Pediatric Patients The following Grade 3 to 4 laboratory abnormalities occurred in greater than 3% of pediatric patients who received treatment with ritonavir either alone or in combination with reverse transcriptase inhibitors: neutropenia (9%), hyperamylasemia (7%), thrombocytopenia (5%), anemia (4%), and elevated AST (3%).